Recent years have seen increasing interests in molecular systems that enable stable encapsulation of a guest molecule in one environment and then controlled release of the guest molecule in a different environment. (Evans, et al. 1999 The Colloidal Domain, 2nd ed.; Wiley-VCH:New York; Holmberg, et al. 2003 Surfactants and Polymers in Aqueous Solution, 2nd ed.; John Wiley & Sons, Ltd: New York; Saito, et al. 2003 Adv. Drug. Delivery Rev. 55,199; Roy, et al. 2010 Prog. Polym. Sci. 35, 278; Guo, et al. 2014 Acc. Chem. Res., 1925.) For example, various systems have been developed for hydrophobic small molecule guests using molecular cages and amphiphilic assemblies. (Liu, et al. 2000 J. Controlled Release 65,121; Gohy, et al. 2003 Macromol. Chem. Phys. 204, 1524; Zhong, et al. 2008 Soft Matter 4, 9; Bae, et al. 2009 Adv. Drug Delivery Rev. 61, 768; Kabanov, et al. 1995 Macromolecules 28, 2303; Allen, et al. 2004 Science 303, 1818; Formina, et al. 2010 J. Am. Chem. Soc. 132, 9540; Chacko, et al. 2012 Adv. Drug Deliv. Rev. 64, 836; Ryu, et al. 2010 J. Am. Chem. Soc. 132, 17227.)
In particular, there is a great need for developing encapsulation systems for proteins as the guest molecules, because imbalance in protein activity is the primary reason for most human pathology. (Gu, et al. 2011 Chem. Soc. Rev. 40, 3638; Walsh Nat. 2010 Biotechnol. 28, 917; Leader, et al. 2008 Nat. rev. Drug Discov. 7, 21.) When a protein is incorrectly overexpressed, common therapeutic approaches include small molecules that bind to the active site of the target and interference RNA molecules that slow down the protein expression. (Leader, et al. 2008 Nat. rev. Drug Discov. 7, 21; Desnick, et al. 2012 Annu. Rev. Genomics Hum. Genet. 13, 307; Parenti, et al. 2013 Int. J. Mol. Med. 31, 11.)
Developing a system for hydrophilic macromolecules, however, has been a significant challenge, since there is no contrast between the bulk and the host interior in water-soluble systems. (Mahmoud, et al. 2011 Bioconjugate. Chem. 22, 1416; Torchilin 2005 Nat. Rev. Drug Discovery 4, 145; Abu Lila, et al. 2009 Expert Opin. Drug Delivery 6, 1297; Eliaz, et al. 2004 Cancer Res. 64, 711; Haag, et al. 2006 Angew. Chem. Int. Ed. 2006, 45, 1198; Angew. Chem. 118, 1218; Murthy, et al. 2003 Proc. Natl. Acad. Sci. U.S.A. 100, 4995; Paramonov, et al. 2008 Bioconjugate. Chem. 19, 911; Kabanov, et al. 2009 Angew. Chem. Int. Ed., 48, 5418; Kabanov, et al. 2009 Angew. Chem. 121, 5524.) Recently, supramolecular approaches in which an assembly responds to the presence of excess proteins are also being explored. (Savariar, et al. 2008 J. Am. Chem. Soc. 130, 5416; Takaoka, et al. 2009 Nat. Chem. 1, 557; Azagarsamy, et al. 2010 J. Am. Chem. Soc. 132, 4550; Mizusawa, et al. 2010 J. Am. Chem. Soc. 132, 729.) On the other hand, when the reduced activity of the protein causes a pathological condition, the options are relatively limited. Gene delivery approaches are promising, but the safety and efficacy of the delivery vehicles have limited their reach so far. (Mastrobattista, et al. 2006 Nat. Rev. Drug Discovery 5, 115; Pack, et al. 2005 Nat. Rev. Drug Discovery 4, 581; Ogris, et al. 1999 Gene Ther. 6, 595; Wattiaux, et al. 2000 Adv Drug Delivery Rev. 41, 201; Hunter Adv. 2006 Drug Delivery Rev. 58, 1523; Tang, et al. 1996 Bioconjugate Chem. 7, 703; Boussif, et al. 1995 Proc. Natl. Acad. Sci. USA 92, 7297.)
An alternative approach is to directly deliver the deficient proteins, which has the advantage of not causing artificial modifications in gene expression. (Gu, et al. 2011 Chem. Soc. Rev. 40, 3638.) Therefore, supramolecular assemblies that can robustly bind to protein molecules and release them in response to a stimulus are of great interest (Scheme 1, FIG. 1). Lysosomal storage diseases are caused by defective enzyme activity in any one of 50 lysosomal enzymes. The disorders, including Tay-Sachs, Fabry, Gaucher, and Pompe diseases, can be treated by delivery of recombinant enzyme to replace the missing enzymatic activity. Although enzyme replacement therapy is efficacious, it is also very inefficient, with less than 1% of the infused enzyme making it to the target tissues. (Desnick, et al. 2012 Annu. Rev. Genomics Hum. Genet. 13, 307.)
Nanoparticles have played an increasingly significant role in diverse fields such as microelectronics, multiphase catalysis, sensing and therapeutics. There have been several nanoscopic systems involving polymeric molecules and proteins, as applicable to protein delivery. (Gu, et al. 2011 Chem. Soc. Rev. 40, 3638.) A commonly reported approach involves covalent conjugation of proteins to polymers using the side chain functional groups or using the initiating/terminating functional group at the chain terminus. (González-Toro, et al. 2013 Eur. Poly. J. 49, 2906.) Non-covalent binding between proteins and polymers have also been approached. Most of these systems use charge complementarity between a polyelectrolyte and the surface charge of the protein as the basis for the formation of the nanoparticle. While this electrostatics-based approach has the advantage of being simple, sterics-based encapsulation has the advantage of providing charge-neutral systems that are often desired for avoiding non-specific interactions based complexities.
Thus, an urgent unmet need remains in developing polymeric nanogels that encapsulate a guest biomolecule stably in one environment and then release it in a different environment in controlled fashion.